We recently found that rats made dependent on morphine show decreased learning and preference for food reward at both two and five weeks post-withdrawal. We also found that animals show increased preference for morphine-associated environmental cues during these same time periods after withdrawal. These place-conditioning paradigms provide a simple model of the dysregulation of reward processing and dysphoria that occurs during opiate abstinence. This dysregulation is generally believed to contribute to elevated preference or seeking for drugs and drug-related stimuli. Our goal is to identify the neural changes that underlie this long-term alteration of reward processing. Preliminary data revealed that neurons in the nucleus accumbens shell, lateral hypothalamus and basolateral amygdala alter their responsiveness to food- or morphine-conditioned stimuli in proportion to the amount of preference expressed. We hypothesize that changed neural function in these areas that regulate ventral tegmental area (VTA) dopamine neurons is critically involved in the associated shift in hedonic values. We further propose that protein kinase A function is altered in these VTA afferents during protracted withdrawal, resulting in compromised plasticity. This change in neural plasticity in the mesocorticolimbic dopamine system is proposed to underlie long term alterations in reward processing. A coordinate set of behavioral and anatomical studies is proposed to test these hypotheses. Together, these studies will identify neural substrates for altered reward processing and hedonic values following chronic drug exposure that may be critical in relapse during long-term abstinence.